Sudden unexplained death (SUD) is a tragic event at any age. The incidence of SUD between the ages of 1 and 35 years is 1-3 events per 100,000 person-years. In addition to loss of life, SUD may herald increased risk for sudden death in surviving first-degree relatives. Genetic disorders of heart rhythm (e.g., channelopathies) and myocardial function (e.g., cardiomyopathies) are blamed for approximately 25% of SUD cases. Screening first-degree relatives of a SUD victim for genetic disease may identify additional family members at risk for sudden death. We propose a three-tiered research study designed to uncover the prevalence and mutational spectrum of channelopathies and cardiomyopathies among cases of sudden death collected by the Sudden Death in the Young (SDY) Case Registry that occur in the absence of epilepsy and have a high likelihood of having a cardiac etiology. In Specific Aim 1, we propose to perform whole genome sequencing of 500 SDY cases coupled with targeted bioinformatics analysis of genes with known involvement in congenital arrhythmia susceptibilities or inherited cardiomyopathies. Whole genome sequencing yields more uniform coverage of coding sequences than exome sequencing and offers opportunities to enable studies of analysis of noncoding variation. In Specific Aim 2, we propose to perform experiments to elucidate the functional consequences of SDY-associated genetic variants in cardiac ion channel genes, especially SCN5A, KCNQ1 and KCNH2. These experiments will generate data essential for assigning the likelihood of pathogenicity for a large class of anticipated variants predisposing to SUD. Finally, In Specific Aim 3, we will determine the frequency with which pathogenic variants in genes associated with congenital arrhythmia susceptibility and cardiomyopathy are inherited from a parent rather than arising de novo. Ascertaining the rate of transmitted versus de novo mutations in SUD cases has important implications for public health and family counseling. As part of our experimental plan, we will also identify new SDY cases through our existing collaboration with Medical Examiner's Offices in Chicago and surrounding counties in Illinois, thereby adding value to the registry and ensuring robust accrual of SDY cases that can be shared across the research network.